Project Summary/Abstract Evidence for environmental manganese (Mn) as a neurodevelopmental toxicant is mounting; yet knowledge about Mn susceptibility remains limited and findings are inconsistent across studies. Our study aims to help clarify childhood environmental Mn neurotoxicity by understanding which domains are most sensitive to Mn exposure across childhood, and by identifying subgroups who are more susceptible to Mn-toxicity by investigating exposure timing, sex differences and interactive and joint effects of multiple metals. The proposed epidemiologic study will use previously measured data from the Public Health Impact of Mixed element Exposure (PHIME) study, comprised of 720 children (ages 10-14 years) with varied airborne exposure to ferro- manganese industry in Italy. Under the mentorship of a multidisciplinary team of experts in environmental epidemiology, neurobehavioral toxicology, exposure biology and mixtures, Julia Bauer (PI) proposes the following aims: 1) identify patterns of Mn-associated neurobehavioral decrements by estimating associations of Mn exposures in early life (measured in deciduous teeth) and adolescence (measured in hair and blood) and multiple Mn-sensitive domain-specific and global neurobehavioral tasks; 2) describe susceptibility factors of Mn neurotoxicity by estimating a) sex-specific associations of Mn in early life and adolescence, with performance on complex visuospatial abilities (measured by the Virtual Radial Arm Maze) as well as on full-scale IQ measured by the Wechsler Intelligence Scale for Children; and b) interactive and joint effects of multiple metals (Mn, Pb, Fe, Cu, Cr) on full-scale IQ. This research will inform the current understanding of Mn effects on children's neurobehavior. It also targets several NIEHS strategic goals: use of technologically advanced exposure data, understanding individual susceptibility across childhood, and accounting for mixture scenarios.